Mice of different genetic backgrounds respond to house dust mite extract with distinct asthma phenotypes and microbial changes

Asthma is a multifactorial chronic inflammatory disease of the lungs with pathophysiological and phenotypic heterogeneity. Approximately 339 million individuals worldwide are currently suffering from asthma according to the Global Asthma Report published in 2018. Asthma risk is shaped by a complex interaction of host genetics and environmental influences, which might both affect the host´s microbiome. The rise in asthma prevalence over the past decades cannot be explained by genetic changes as these occur over longer periods of time. Thus, it is assumed that changing environmental influences affect the host’s microbiome in first instance. This study aimed to obtain a first insight into the relative contribution of the host’s genetics versus the host’s microbiome in shaping asthma phenotypes. After experimental asthma induction by applying house dust mite (HDM) extract in four mouse strains of different genetic backgrounds (A/J, BALB/cJ, C57BL/6J and C3H/HeJ) the asthma phenotypes and the gut and lung microbial compositions were evaluated. HDM treatment induced distinct phenotypes in the four mouse strains. C3H/HeJ was identified as a strong Th2-prone, eosinophilic phenotype with pronounced goblet cell hyperplasia and high IgE levels. A/J displayed a similar phenotype with slightly lower levels of Th2-cytokines, whereas BALB/cJ were characterized by a Th2-low phenotype with an overall reduced severity. C57BL/6J showed an intermediate phenotype with higher IL-17A levels in the BAL supernatant than in the remaining strains. Furthermore, it was found that the microbial composition in the gut did not differ among the strains and was also not altered after the induction of experimental asthma. Aside from the A/J and C57BL/6J, the lung microbial composition in the healthy mice showed no marked variation among the strains. However, the abundance of Proteobacteria in the lungs of all HDM-treated groups was increased. Comparing the beta diversity measures of the PBS versus the HDM group revealed a significant difference in the microbial profile only for the C3H/HeJ strain. These results suggest a contribution of the genetic background on the developing asthma phenotypes. While, the genetics appear to have only a minor impact on the microbial composition in healthy mice. This changes in the disease state where the lung microbial composition differs among mice of different genetic backgrounds. The obtained results on the microbial composition are purely descriptive, therefore future studies in germ-free mice, including high-resolution sequencing, are required to identify the relevance of single bacteria on lung health.


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